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Method and composition for treating heart failure

a heart failure and composition technology, applied in the field of cardiac therapy, can solve the problems of heart failure as a leading case of death and disability, major health care costs items, and conventional treatments, and achieve the effects of improving clinical state, reducing the risk of heart failure, and improving the clinical state of left ventricular hypertrophy and myocardial contractile sta

Active Publication Date: 2009-04-09
THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]Another object of the present invention is to provide a new treatment for heart failure which accompanies the use of an angiotensin converting enzyme inhibitor, such as captopril (a standard treatment for the management of heart failure) with phenylbutyrate. While use of angiotensin converting enzyme inhibitors alone has been found to improve clinical state, the gene expression changes associated with heart failure are minimally modified. Left ventricular hypertrophy and myocardial contractile state are not improved. Adding phenylbutyrate to angiotensin converting enzyme inhibitor results in reversal of numerous gene expression changes, amelioration of left ventricular hypertrophy and contractile dysfunction. Thus, simultaneous administration of an angiotensin converting enzyme inhibitor to stabilize hemodynamics together with phenylbutyrate to modulate gene expression is demonstrated in the present invention to provide an effective method for the treatment of heart failure.

Problems solved by technology

Heart failure is a leading case of death and disability.
Hospitalization and long-term care for this condition represent major health care costs items.
Conventional treatments for heart failure are designed to stabilize disease progression and are primarily limited to the administration of an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker, beta adrenergic blocker, or diuretic.
This results in decreased workload on the heart in patients with heart failure.
This treatment may temporarily reduce clinical symptoms of heart failure, however, does not effectively treat the underlying disease and the long-term outlook for heart failure patients remains poor.
However, myocardial dysfunction involving depressed myocardial contractility and cardiac enlargement due, in large part, to pathologic gene expression remains unresolved.
Histone deacetylase inhibitors are substances causing inhibition of the activity of histone deacetylase, resulting in hyperacetylation and leading to chromatin relaxation and wide scale changes of gene expression.
However, thus far, phenylbutyrate has not been used for the treatment of heart failure.

Method used

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  • Method and composition for treating heart failure
  • Method and composition for treating heart failure
  • Method and composition for treating heart failure

Examples

Experimental program
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Effect test

example 1

A Combined Histone Deacetylase Inhibitor and Angiotensin Converting Enzyme Inhibitor Treatment is Effective for Heart Failure

[0048]Adult male spontaneously hypertensive rats (SHR) rats were purchased as retired breeders from Taconic Inc and boarded in the animal facility at the Boston VA Healthcare system until the time of study (18 to 24 months of age). Each rat was caged alone and allowed free access to chow and water. Animals were monitored several times per week for evidence of tachypnea and labored respiration; when these clinical findings were clearly in evidence, animals were either killed and studied or treated with captopril and / or phenylbutyrate. Groups of animals were treated by adding the angiotensin converting enzyme inhibitor captopril to the drinking water (2 g / L to drinking water) and / or phenylbutyrate to the drinking water (6 g / L to the drinking water; sodium 4-phenylbutyrate (Triple Crown America, Inc.)) when clinical evidence of impaired cardiac function was detec...

example 2

The Ventricular Mass Increases with Heart Failure

[0050]There is an increase in left and, to a greater extent, right ventricular weight with heart failure in SHR rats. See Table 1 and FIGS. 4A and 4B.

[0051]Table 1 (below) summarizes body weight, cardiac chamber weight, and ratios with and without treatment. Referring to Table 1, four groups of six SHR / group were examined: non-treated SHR with heart failure (SHR-F), age matched controls without heart failure (SHR-NF), and SHR with heart failure treated with the angiotensin converting enzyme inhibitor captopril (2 g / L in drinking water) (SHR-F+C) or captopril combined with the histone deacetylase inhibitor phenylbutyrate (6 g / L in the drinking water) for 30 days (SHR-F+CP). The results show changes in the pathological tissue weight between the SHR with heart failure (SHR-F) and non-failing SHR groups (SHR-NF), and the group treated with phenylbutyrate, and, to a far lesser extent, the captopril treated group. It was observed that SHR r...

example 3

Effect of Phenylbutyrate and Captopril Treatment on Myocardial Muscle Function of SHR with Heart Failure

[0053]At the time of sacrifice, left ventricular papillary muscles were dissected free and mounted in an isolated muscle bath containing oxygenated physiologic solution for assessment of mechanical function. Muscle mechanics were measured under computer control of force or length of the preparation. Force and length data were sampled at a rate of 1 kHz and stored on disk for later analysis.

[0054]Table 2 (below) summarizes the changes in left ventricular papillary muscle mechanical function obtained from SHR with heart failure (SHR-F), age-matched non-failing SHR (SHR-NF), and SHR with heart failure treated at the time of failure with captopril (SHR-F+C; 2 g / l in the drinking water) or captopril and phenylbutyrate (SHR-F+CP; 6 g / l in the drinking water). Treatment was continued for 30 days and then the animals studied.

TABLE 2AT+dT / dtRT1 / 2V1.0Kwm(g / mm2)(g / mm2 / s)(ms)(muscle length / s)...

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Abstract

A method and composition for treating, preventing or ameliorating heart failure, cardiac hypertrophy, and / or myocardial dysfunction includes administering a therapeutically effective amount of a HDAC inhibitor, such as phenylbutyrate, in combination with an ACE inhibitor, such as captopril.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority on prior U.S. Provisional Application Ser. No. 60 / 960,598, filed Oct. 5, 2007, which is hereby incorporated herein in its entirety by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The work leading to the present invention was supported by one or more grants from the U.S. Government, and specifically the VA merit review grant entitled “Restoration of Function in the Failing Heart”. The U.S. Government therefore has certain rights in the invention.FIELD AND BACKGROUND OF THE INVENTION[0003]The present invention is generally directed to cardiac therapy, and more particularly to treating, preventing, or ameliorating heart failure and / or cardiac hypertrophy, and / or dysfunction by reactivating silenced adult cardiac gene expression.[0004]Heart failure is a leading case of death and disability. Hospitalization and long-term care for this condition represent major health car...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/40A61K31/216A61P9/00
CPCA61K31/216A61K31/40A61K45/06A61K2300/00A61K31/192A61K31/401A61P9/00A61P9/04
Inventor BROOKS, WESLEY W.BING, OSCAR H.L.
Owner THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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